Notas de antihiperlipidemics (colon)

Apo b 100: IDL ?

Apo b 48: chilomicrons
LPA lipoprotein aumenta la oxidacin de los ldl, por eso ms riesgo de
arterosclerosis.
Hiperlipidemia y hipoproteinemia
o Hiperlipemia- mucho triglicridos.
Pancreatitis
Arterosclerosis
Apolipoproteinas: binds lipids transporting them
through the lymphatic and circulatory systems.
Son amphipaticas.
Cofactores de ez:
- Apo c 2: para la lipoproteina lipasa que rompe
los trigliceridos a acidos grasos
- Apo a 1: para la lecithin colestrol
acetiltransferase que permite el transporte
de cholesterol entre las diferentes
lipoproteinas
Receptor ligands: apoproteina presente le
permiten al hgado decidir si lo va a degradar o
guarder.
Apo b 100: LDL, las que son ligandos para
interactuar con receptors de lipoproteinas en
tejidos
Apo E: para LDL receptors
Apo A 1: para HDL

Colesterol: deseable 200, borderline high 240, alto mas de eso

Triglicridos: 150 normal, borderline high 200, alto 200-500, bien alto
>500

Chylomicronemia por lpl o apoc2 deficiency

o Triglicridos en 2000
Hypertrigliceridemia familiar:
o Aumento en niveles de chilomicrons y vldl
Severo ambos aumentados, moderado puede que los chilo
si o no
Para las genticas el principal tratamiento es dieta???
Hypertrigliceremia:
o Desorden gentico en que el ldl es dos veces mas alto.
o Mucho vldl y/o ldl

o Se hace dieta
Familial Dysbetalipoproteinemia
o Bajos LDL; chilomicrones y vldl acumulados
o La lipasa heptica rompe los acidos grasos pero como depende
de interaccion con receptores no se pueden producir los LDL (no
se tienen los remanentes)
Hypertrigliciremia:
o Defectos en receptor
o Hay tratamientos que aumentan expresin de receptores, pero
hay pacientes que aumentar los receptores no hace nada.
Hypercolesterolemias:
o Famimiar FH
Lpa:
o Famimial disorcer
o NIACINA recuce los niveles de esta protena.
Dislipidemias se tratan primero con DIETA
o Fructosa aumentan los vldl
o Omega-3 fatty acids found in fish oils, but not those from plant
sources, activate peroxisome proliferator-activated receptoralpha (PPAR-) and can induce profound reduction of
triglycerides in some patients.
Lipoproteinas: empaques de grasa con protenas.
HDL: tiene mucha protena, puede cargar poco colesterol.
LDL: tiene colesterol bien alta

Dietary Management of Dyslipidemias

- Dietary measures initiated first, unless the patient has evident
coronary or peripheral vascular disease, may obviate the need for
drugs.
- Patients familial with familial combined hypercholesterolemia or
hyperlipidemia always require drug therapy.
o Cholesterol, saturated and trans-fats are the principal factors
that increase LDL,
o Whereas total fat, alcohol, and triglycerides. Excess calories
increase Sucrose and especially fructose increase VLDL.
o Alcohol can cause significant hypertriglyceridemia.
o Increases hepatic secretion of VLDL. Synthesis and secretion of
VLDL are increased by excess calories.
- Omega-3 fatty acids found in fish oils (not those from plant sources)
activate peroxisome proliferator-activatedreceptor-alpha (PPAR-) and
can induce profound reduction of triglycerides in some patients.
o They also have anti-inflammatory and antiarrhythmic activities.

Desordenes
Although LDL is still the primary target of treatment, reducing the
levels of VLDL and IDL is also important.
Inversely related to levels of HDL, and is modified by other risk
factors.
Evidence from clinical trials suggests that LDL cholesterol levels of 60
mg/dl may be optimal for patients with coronary disease. Ideally,
triglycerides should be below 120 mg/dl.

Hyperlipidemias Abnormalities in lipid metabolism or plasma lipid

transport or a disorder in the synthesis and degradation of plasma
lipoproteins.
Metabolic disorders that involve elevations in any lipoprotein species
are termed hyperlipidemias or Hyperlipoproteinemias [is a common
disorder. It causes an inability to break down lipids or fats in the body,
specifically cholesterol and triglycerides.]
o Plasma lipids are transported in macromolecular complexes
called lipoproteins.
o Disorders in the below-described metabolisms can be divided
into three main groups
Hypercholesterolemia: elevated LDL
Hypertriglyceridemia: elevated chylomicrons (or VLDL)
Primarily associated with pancreatitis
Mixed hypercholesterolemia and
hypertriglyceridemia: elevated VLDL and LDL or IDL
o Can be the result of genetic deficiencies
o Can be the result of other conditions or diseases
Hyperlipemia denotes increased levels of triglycerides.
The two major clinical sequelae of hyperlipidemias are:
o Acute pancreatitis: occurs in patients with marked hyperlipemia.
o Atherosclerosis
Lipoprotein: Macromolecular assembly that contains both lipids and
proteins.
Transport the apolar, and otherwise water-insoluble cholesterol and
triglycerides through the bloodstream
Major components:

o Cholesterol
o 2025% of total daily cholesterol production occurs in the liver
o other sites of high synthesis rates: intestines, adrenal glands,
and reproductive organs.

 Key intermediate in the biosynthesis of a variety of endogenous steroids (e.g.

aldosterone, testosterone etc.)

Taken up by food or biosynthesized from acetyl Co-A
Esterified to cholesterol esters by lecithin-cholesterol acyltransferase (LCAT).
Present in lipoproteins as cholesterol and/or cholesterol ester
o Triglycerides: supply energy for the body. Triglycerides either meet
immediate energy needs in muscles or stored as fat for future energy
requirements
Esters of glycerol
Accumulate in adipose tissue as energy storage
After hydrolysis catalyzed by lipases, fatty acids are oxidized and
provide energy
Apolipoproteins: Bind lipids transporting
Bind to cellular receptors Types:
Apo B-48: formed in the intestine, found in chylomicrons (primera
liporpoteina donde se almacenan los lipidos que se consumen) and their
remnants.
ApoB-48, synthesized only by intestinal epithelial cells, unique to
chylomicrons. ApoB-48 returns to the liver as part of the chylomicron
remnant, where it is endocytosed and degraded.
Apo B-100: synthesized in the liver, found in VLDL, VLDL remnants (IDL),
LDL and Lp(a) lipoproteins. (El higado toma los remanentes que llegaron
al higado y puede formar formas transportables. como se entra al sistema
circulatorio con la apob 100 en vldl ( se hace en higado) vldl se rompe por
lipasas a idl. todas con apob.)
ApoB-100 is synthesized by the liver and incorporated into
VLDL and intermediate-density
lipoproteins (IDL) and LDL, which are products of VLDL
catabolism.
Apo A-I: cofactor for lecithin-cholesterol acyltransferase. Permite
transferencia de cholesterol y permite interaccion con receptors de HDL.
Apo C-II: required cofactor for LIPOPROTEIN LIPASE
Triglycerides are removed in extrahepatic tissues through a pathway
shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL)
system. interaction requires apoC-II as an absolute cofactor
The absence of functional LPL or functional apoC-II prevents the
hydrolysis of triglycerides severe hypertriglyceridemia and pancreatitis
during childhood or even infancy (chylomicronemia syndrome)
Apo C-III: inhibitor of lipolysis.
Apo E: required for uptake of lipoprotein remnants by the liver.

Types of Lipoproteins/metabolism
o Chylomicrons (TGs): Formed in GI tract from dietary triglycerides.

 Exogenous pathway
Transport dietary (exogenous) triglycerides to the adipose and muscle
tissue degradation by lipoprotein lipase (present on adipose and
muscle tissue) into free fatty acids and remnants reduces
triglyceride content
Free fatty acids available for storage or energy
Remnants dietary cholesterol(/esters) in remnants are transported to
liver
o VLDL (TGs and cholesterol): Endogenously synthesized in liver.
Degraded by lipoprotein lipase (LPL) into free fatty acids (FFA) for storage in
adipose tissue and for oxidation in tissues such as cardiac and skeletal
muscle.
Transport endogenous triglycerides to the adipose and muscle
tissue degradation by lipoprotein lipase formation of free
acids and IDL (reduces triglyceride content).
IDL (TGs, cholesterol); and LDL (cholesterol): Derived from VLDL
hydrolysis by LPL. Normally, about 70% of LDL is removed from plasma by
hepatocytes.
Endogenous pathway
IDL
About 60-70% of cholesterol is in LDL
LDL transports endogenous cholesterol to hepatic and extrahepatic cells.????
LDL binds to LDL-receptors of extrahepatic
tissues cholesterol is released into cells via endocytosis.
o When extrahepatic cells require more cholesterol increased
biosynthesis of LDL-receptors;
o When excess cholesterol is present suppression of biosynthesis of
LDL- receptors and cholesterol.
Can also bind to LDL-receptors in the liver clearance from plasma.
When cholesterol concentration in the liver increases cholesterol biosynthesis is
inhibited as well as production of hepatic LDL-receptors
o

HDL (protective): Exert several anti-atherogenic effects. They participate in retrieval

of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins,
removes cholesterol from tissues to be degraded in liver.
Synthesized in the liver and intestine
Initially exists as a phopholipid disc containing apolipoproteins
Accepts free cholesterol
Cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT) cholesterol
becomes
less polar moves to the inside of HDL subsequent uptake of more cholesterol
Cholesterol esters are finally transferred from HDL to VLDL or IDL.

 Al tener muchos lipidos el higado trata de excretarlo con sales biliares, asi que
secreta muchas sales biiares.
Pancreatitis: Inflammation of the pancreas. The pancreas is a large organ behind
the stomach that produces digestive enzymes.
The most common causes of acute pancreatitis are gallstones and heavy
alcohol use.
o High levels of blood fats (Hypertriglyceremia).
o Smoking increases the risk of pancreatitis.
Complications may include infection, bleeding, diabetes, or problems with
other organs.
Atherosclerosis Underlying cause for CHD
Accumulation of lipids in the arteries thickening of the arterial wall plaque
formation thrombosis
Hyperlipidemia is a major cause of atherosclerosis.
Atherosclerotic plaques:
o Foam cells: Transformed macrophages filled with cholesteryl esters.
Result from receptor mediated endocytosis of lipoproteins
lesions slowly occludes coronary vessels, clinical symptoms are
precipitated by rupture of unstable atheromatous plaques, leading
to activation of platelets and formation of occlusive thrombi.
The major risk factor includes:
o Hyperlipidemia (hypercholesterolemia).
o Low levels of high-density-lipoprotein (HDL).
High concentration of CE change macrophages into foam cells accumulation of
foam cells: formation of fatty streaks deposition of lipids, lipoproteins etc. leads to
larger plaques eventually leads to fibrous plaques Ultimately leads to
thrombosis and occlusion.
Chylomicrons Formed in the intestine, carry triglycerides of dietary origin,
unesterified cholesterol, and cholesteryl esters through to the bloodstream.
High fat content (98-99%), 85% is from dietary triglycerides.
o The ratio of triglycerides to cholesterol is 10 or greater.
Chylomicron Remnants: After LPL-mediated removal of much of the dietary
triglycerides, the chylomicron remnants, which still contain all of the dietary
cholesterol, detach from the capillary surface and within minutes are removed
from the circulation by the liver.
o remnants are processed by hepatic lipase (HL), further reducing the
remnant triglyceride remnants uptake is mediated by hepatic LDL
receptor (one mechanism by which nascent HDL (precursor) are
generated)
o Chylomicron remnants are not precursors of LDL, but the dietary

cholesterol delivered to the liver by remnants increases plasma LDL levels

by reducing LDL receptor-mediated catabolism of LDL by the liver.
Very Low Density Lipoprotein
Produced in the liver when triglyceride production is stimulated by an
increased flux of free fatty acids or by increased de novo synthesis of fatty
acids by the liver.
o VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for
storage in adipose tissue and for oxidation in tissues such as cardiac and
skeletal muscle.
Depletion of triglycerides produces remnants (Intermediate Density Lipoproteins).
o 40-60% undergoes are cleared from the plasma by the liver via interaction
with LDL receptors.
o LPL and HL convert the remainder of the IDL to LDL by removal of additional
triglycerides.
This process explains the beta shift phenomenon (increase of LDL
(beta-lipoprotein) in serum as hypertriglyceridemia subsides). En
personas con trigliceridos altos, la liporpoteina alta es chilomicrones,
que tienen apob 48. Al tartar una personas con trigliceridos altos
ocurre lo siguiente, hay aumento en los ldl porque el higado los usa
para hacer vldl, al comenzar a disminuir aumetna el rate de vldl a
chilomicrones, vldl son los precursors de ldl. (SHIFT, EFECTO INCIAL)
Hay mas apo b 100 qua apo b 48 en la sangre. SI TRATAMOS SOLO
TRIGLICERIDOS SUBE LDL, SE DEBEN TRATAR AMBOS. AL PRINCIPIO
DE TRATAR TRIGLICERIDOS LDL SUBE.
Increased levels of LDL can also result from increased secretion of
VLDL and from decreased LDL catabolism.

Low Density Lipoproteins All of the LDL is derived from VLDL.

o LDL-apolipoprotein B complex - recognized by the LDL receptor in
peripheral tissues.
Cholesteryl esters from LDL are hydrolyzed, yielding free
cholesterol for the synthesis of cell membranes. Cells also obtain
cholesterol by synthesis (formation of mevalonic acid by HMG- CoA
reductase).
Production of this enzyme and of LDL receptors is transcriptionally regulated
by the content of cholesterol in the cell.
o Plasma clearance of LDL particles is mediated primarily by LDL receptors.
The most common cause of autosomal dominant

hypercholesterolemia involves mutations of the LDL receptor gene

The most effective dietary alteration (decreased consumption of
saturated fat and cholesterol) and pharmacological treatment (statins)
for hypercholesterolemia act by enhancing hepatic LDL receptor
expression.
LP(a) Lipoprotein: The risk of coronary disease is strongly related to the
level of Lp(a).
is formed from LDL and the Apo(a) protein, linked by a disulfide bridge.
o Levels vary from nil to over 2000 nM/L and are determined chiefly
by genetic factors
can be found in atherosclerotic plaques and may also
contribute to coronary disease by inhibiting thrombolysis
o Levels are elevated in certain inflammatory states
o Lpa transports the more atherogenic proinflammatory oxidized
phospholipids, which attract inflammatory cells to vessel walls
and leads to smooth muscle cell proliferation.
High Density Lipoprotein
are synthesized by the liver and the intestine.
Exerts several anti-atherogenic effects.
o They participate in retrieval of cholesterol from the artery wall.
o Inhibit the oxidation of atherogenic lipoproteins.
o Platelet anti-aggregatory--Anticoagulant.
o Profibrinolytic activities
o recoge colesterol a medida que pasa los vasos sanguineos recogiendo
lipidos
Both androgens and estrogens affect Hepatic Lipase gene expression.
o Androgens increase HL activity.
o Estrogens reduce HL activity.
Accounts for the lower HDL values observed in men than in women.
hombres menos hdl porque andrginos aumentan la degradacion
estrogen reduce la actividad de lapidas hepatica.
protective effect: participation in reverse cholesterol transport.
o HDL levels relate inversely to atherosclerosis risk.
Low levels of HDL (HYPOALPHALIPOPROTEINEMIA) are an independent risk
factor for atherosclerotic disease and thus are a potential target for
intervention.
Cigarette smoking It is associated with reduced levels of HDL, impairment of
cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation
of lipoproteins, and stimulation of thrombogenesis.
Diabetes, also a major risk factor, is another source of oxidative stress.